This application presents a proposal to study the mechanisms by which histamine tachyphylaxis develops in canine tracheal smooth muscle. In vitro experimentation will be employed. Isolated tissue strips will be suspended in tissue baths so that the physiologic response of contractile force development can be correlated with the biochemical changes occurring in the tissue. The role of histamine receptors prostaglandins, cyclic nucleotides, cholinergic function and calcium in the development of tachyphylaxis will be examined. Preliminary studies have indicated that prostaglandins exert a major control in the development of acute histamine tolerance. Therefore, the nature of their role will be examined in detail by such procedures as the addition of exogenous prostaglandins, the testing of inhibitors of the process of prostaglandin synthesis and inhibitors of the interaction with prostaglandin receptors. Methods will be further expanded to place additional emphasis on bioassay and gas chromatography, to allow for the isolation, identification and quantitation of the prostaglandin(s) involved. Emphasis is also to be placed on the biochemical site of prostaglandin involvement. These studies on an established state of altered sensitivity to histamine will be beneficial in aiding the understanding of pulmonary smooth muscle function and the mechanisms which control its responsiveness. These data while providing basic information, have a significant potential for providing insight into clinical conditions of increased histamine sensitivity where mechanisms of acute tolerance development may be defective.